Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered the leading cause of premature death (Blair, 2009). Rates of physical inactivity continue to increase along with health care costs to treat CVD. Despite these disturbing trends, the mechanisms by which a sedentary lifestyle leads to CVD are not fully known. CVD is associated with increased sympathetic nervous system activity and overactivity of a brainstem region known as the rostral ventrolateral medulla (RVLM) (Sved et al., 2003; Guyenet, 2006). Sympathoexcitatory responses to direct activation of the RVLM are enhanced in sedentary versus physically active animals (Mischel and Mueller, 2011). These data suggest that a sedentary lifestyle may contribute to the development of CVD by increased sensitivity of RVLM neurons. Our long term goal is to understand the central sympathetic mechanisms by which physical inactivity contributes to the development of CVD. This is an important clinical, economic and public health care problem. The overall objective of this application is to define the mechanisms and time course by which physical inactivity increases, and physical activity prevents over-activation of presympathetic neurons in the RVLM. The central hypothesis is that enhanced sympathoexcitation observed in sedentary animals is due to structural and functional neuroplasticity in RVLM neurons that regulate sympathetic activity. We will test this central hypothesis by focusing on the following distinct, bt interrelated specific aims: 1) Determine the functional mechanisms by which sedentary conditions enhance neuronal activity in rostral regions of the RVLM. 2) Define structural mechanisms by which sedentary conditions enhance activation of bulbospinal neurons in rostral regions of the RVLM. 3) Delineate molecular and cellular mechanisms by which sedentary conditions produce enhanced endogenous excitatory neurotransmission in rostral regions of the RVLM. Our proposal provides a compelling rationale to understand the underlying molecular, cellular and anatomical mechanisms by which physical inactivity alters neurotransmission in the RVLM. Without this knowledge our understanding of how physical inactivity increases the incidence of cardiovascular disease and how exercise prevents or rescues the inactivity phenotype is extremely limited. This problem has significant social and economic implications since physical inactivity is described as the biggest health care problem of the 21st century(Blair, 2009). We expect to establish at the end of this five year project the extent to which physical activity and inactivity impact regulation of a brain region that is critical to norml and pathophysiological increases in sympathetic nervous system activity. These studies may improve the lives of individuals who are unable to exercise or find difficulty exercising by 1) the development of new treatment options for CVD; 2) increasing public awareness of the detrimental effects of a sedentary lifestyle; and 3) indirectly reducing escalating health care costs associated with physical inactivity.